The Development of a High Throughput Whole Brain Alzheimer's Disease Drug Screening Pipeline

高通量全脑阿尔茨海默病药物筛选流程的开发

• 批准号: 10161681
• 负责人: Timothy M. Ragan
• 金额: $ 81.45万
• 依托单位: TISSUEVISION, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161681
• 关键词: 3-Dimensional; Address; Affect; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid deposition; Animal Model; Atlases; Automobile Driving; Back; Biological Assay; Biological Markers; Biotechnology; Brain; Brain Mapping; Brain imaging; Brain region; Central Nervous System Diseases; Clinic; Collaborations; Complex; Contracts; Data Set; Development; Disease; Disease Progression; Drug Screening; Etiology; Evaluation; Funding; Generations; Goals; Growth; Human; Image; Institutes; Kinetics; Label; Late Onset Alzheimer Disease; Measures; Methodology; Methods; Microscopic; Modeling; Molecular; Molecular Analysis; Neurodegenerative Disorders; Neurosciences; Optics; Pharmacologic Substance; Phase; Phenotype; Positioning Attribute; Preclinical Testing; Production; Proteins; Protocols documentation; Rapid screening; Recording of previous events; Research; Research Contracts; Research Personnel; Rodent; Rodent Model; Sampling; Senile Plaques; Services; Slide; Stains; Standardization; The Jackson Laboratory; Therapeutic; Therapeutic Intervention; Thiazines; Time; Tissues; United States; Validation; analysis pipeline; assay development; base; brain research; clinically translatable; combinatorial; commercialization; cost; density; drug development; effective therapy; experience; flexibility; human old age (65+); image processing; imaging platform; improved; instrumentation; interest; member; microscopic imaging; next generation; novel; secondary analysis; symposium; synergism; tissue processing; tomography; tool; two-photon

Project Summary Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting roughly 1 in 10 people over the age of 65. In 2017, the total cost of AD in the United States was estimated at $259 billion and is predicted to climb to $1.1 trillion by the year 2050. Despite enormous efforts invested in finding a cure, it has proven extremely difficult to develop treatments for AD. Contributing factors behind this difficulty is that AD is a complex, multifactorial disease, occurring over decades, and as CNS disease, is very difficult to study directly in the clinic. To address this challenge, the 2015 AD research summit set a goal to create and characterize a new generation of improved research models that would more faithfully reflect AD in humans. These new models hold enormous promise, but unfortunately contemporary tools are incomplete at best. Phenotypic whole brain methodologies, while providing a critical overview of the temporal and spatial progression of AD, have little corresponding molecular information. Meanwhile, in depth molecular methods remain confined to studying small portions of the brain due to time or cost limitations. This lack of an overview of the molecular mechanisms driving the spread of AD across the brain – a central aspect of AD in humans – leaves a crucial gap in our understanding of the etiology of the progression of AD and hinders the development of effective treatments. To bridge this gap, this proposal will build a flexible imaging and tissue processing platform to rapidly characterize AD rodent models that provides whole brain information while at the same time extends access to in-depth molecular information to facilitate crucial clinical translatability. This proposal combines teams from TissueVision and the NIA-funded MODEL-AD Center at The Jackson Laboratory who are experts in neuroscience, optical microscopy, imaging assays, and who have a successful commercialization history. Together, we will build on a set of impressive preliminary results mapping AD progression in whole brain datasets and produce a drug development pipeline to provide automated brain region mapping and combinatorial markers of AD pathology. We believe the synergy between instrumentation, biological assay development, and the next generation of AD research models represents an ideal partnership to develop next generation tools that hold the promise of finally developing effective treatments for AD.

项目摘要 阿尔茨海默氏病（AD）是一种使人衰弱的神经退行性疾病， 65岁以上的10人。2017年，美国AD的总成本为 估计为2590亿美元，预计到2050年将攀升至1.1万亿美元。尽管 投入了巨大的努力来寻找治愈方法，但事实证明， 治疗AD。这种困难背后的促成因素是AD是一种复杂的， 多因素疾病，发生了几十年，作为中枢神经系统疾病，是非常难以研究的 直接在诊所。 为了应对这一挑战，2015年AD研究峰会设定了一个目标， 描述新一代改进的研究模型， 反映人类的AD。这些新模型有着巨大的潜力，但不幸的是， 现代工具充其量是不完整的。表型全脑方法，而 提供了一个关键的概述的时间和空间进展的AD，有很少 相应的分子信息。与此同时，深入的分子方法仍然存在， 由于时间或成本的限制，它仅限于研究大脑的一小部分。这种缺乏 概述了驱动AD在大脑中传播的分子机制- a 人类AD的核心方面-在我们对病因学的理解中留下了一个关键的空白 AD的进展，并阻碍了有效治疗的发展。弥合 该提案将建立一个灵活的成像和组织处理平台， 快速表征AD啮齿动物模型，提供全脑信息， 同时扩展了深入的分子信息，以促进关键的临床 可译性 该提案结合了TissueVision和NIA资助的MODEL-AD中心的团队 在杰克逊实验室，他们是神经科学，光学显微镜，成像 分析，并且具有成功的商业化历史。我们将共同建立一个 一组令人印象深刻的初步结果，在全脑数据集中绘制了AD进展， 产生药物开发管道，以提供自动化的大脑区域映射， AD病理学的组合标志物。我们相信仪器之间的协同作用， 生物测定的发展，和下一代的AD研究模型代表 一个理想的合作伙伴关系，以开发下一代工具， 开发有效的AD治疗方法。